Pyridopyrrolobenzheterocycles

ABSTRACT

The compounds are prepared by cyclizing compounds of formula II ##STR2## wherein R 2  is R 1  or acyl. The latter compounds are prepared by reacting 4-piperidones with compounds of formula III in the presence of a reducing agent ##STR3## or with compounds of formula VI ##STR4##

CROSS REFERENCE TO RELATED APPLICATION

This is a division, of application Ser. No. 755,121, filed Dec. 28,1976, now U.S. Pat. No. 4,115,577, which in turn is a division ofApplication Ser. No. 586,746, filed July 13, 1975, now U.S. Pat. No.4,013,652 which in turn is a division of Application Ser. No. 357,528,filed May 7, 1973, now U.S. Pat. No. 3,914,421, which is acontinuation-in-part of Application Ser. No. 263,766, filed June 9,1972, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novelpyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepines and-benzoxazepines, novelpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazines and -benzoxazines,novel pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzothiazepines and-benzoxazepines, novelpyrido[3',4':4,5]pyrrolo[3,2,1-kl][5,1]benzothiazocines and-benzoxazocines, and novel intermediates therefor.

U.S. Pat. No. 3,299,078 disclosespyrido[3',4':4,5]pyrrolo[3,2,1-hi]indole and -[3,2,1-ij]quinoline of theformula: ##STR5## where A is methylene or ethylene, and certainsubstituted derivatives thereof. According to the disclosure, thecompounds have analgesic, anti-pyretic, anti-inflammatory,antiserotonin, and CNS stimulant activity. The patent also disclosesintermediates having the formula: ##STR6## where A is methylene orethylene, and cyclization of these intermediates to form thepyridopyrroloindoles and -quinolines.

SUMMARY OF THE INVENTION

This invention is a class of novel compounds having the formula:##STR7## where X is O, S, ##STR8## or SO₂ ; n is 0 or 1;

m is 0 or 1;

the R's are the same or different and are H or CH₃, and one of them canbe C₂ -C₉ alkyl, phenyl, C₇ -C₁₀ phenylalkyl, furyl, thienyl, pyridyl,phenyl or C₇ -C₁₀ phenylalkyl substituted on adjacent ring carbon atomswith methylenedioxy, or phenyl or C₇ -C₁₀ phenylalkyl substituted on thering with 1, 2 or 3 substituents individually selected from methoxy,ethoxy, bromine, chlorine, fluorine, trifluoromethyl and C₁ -C₄ alkyl;when X is S and m is 0 one R on the group --RCR-- can be --OCH₃ ; andwhen X is S and m is 1, the R on the group (CHR)_(m) can be --OCH₃.

R¹ is hydrogen, C₁ -C₄ alkyl, C₃ -C₅ alkenyl, C₃ -C₅ alkynyl, C₃ -C₆cycloalkyl, C₂ -C₄ alkoxycarbonyl, trifluoroacetyl or substituted C₁ -C₄alkyl where the substituent is C₃ -C₆ cycloalkyl, phenyl, phenylsubstituted on adjacent carbon atoms with methylenedioxy, or phenylsubstituted with 1, 2 or 3 substituents individually selected frommethoxy, ethoxy, bromine, chlorine, fluorine, trifluoromethyl and C₁ -C₄alkyl; and

Z is H, Cl or CH₃ ; and their pharmaceutically suitable salts.

The compounds are useful as sedatives. Some of the compounds also haveantidepressant, antihypertensive and antibacterial activity.

The invention includes the novel intermediates of formulae II, III, andVI and the process of making the compounds of formula I by cyclizationof compounds of formula II as described hereinbelow.

The invention also includes pharmaceutical preparations containing thecompounds of formula I and their pharmaceutically suitable salts, andmethods of producing sedation in warm-blooded animals by administrationthereof.

DESCRIPTION OF THE INVENTION Nomenclature

Formula I encompasses eight novel ring systems: ##STR9##2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine##STR10##2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzoxazepine##STR11##1,2,7,8,9,10-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazine##STR12##1,2,7,8,9,10-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazine##STR13##1,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzothiazepine##STR14##1,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepine##STR15##2,3,9,10,11,12-hexahydro-1H,5H-pyrido[3',4':4,5]pyrrolo[3,2,1-kl][5,1]benzothiazocine##STR16##2,3,9,10,11,12-hexahydro-1H,5H-pyrido[3',4':4,5]pyrrolo[3,2,1-kl][5,1]benzoxazocine

In formulae Ia-Ih, rings C and D constitute the pyrrole and pyridinerings, respectively. Rings A and B together constitute the1,5-benzothiazepine system in Ia, the 1,5-benzoxazepine system in Ib,the 1,4-benzothiazine system in Ic, the 1,4-benzoxazine system in Id,the 4,1-benzothiazepine system in Ie, the 4,1-benzoxazepine system inIf, the 5,1-benzothiazocine system in Ig, and the 5,1-benzoxazocinesystem in Ih.

The corresponding intermediates of formula II are named as follows:##STR17## IIa:2,3,4,5-tetrahydro-5-[(4-piperidylidene)amino]-1,5-benzothiazepine IIb:2,3,4,5-tetrahydro-5[(4-piperidylidene)amino]-1,5-benzoxazepine

IIc: 3,4-dihydro-2H-4[(4-piperidylidene)amino]-1,4-benzothiazine

IId: 3,4-dihydro-2H-4[(4-piperidylidene)amino]-1,4-benzoxazine

IIe: 1,2,3,5-tetrahydro-1[(4-piperidylidene)amino]-4,1-benzothiazepine

IIf: 1,2,3,5-tetrahydro-1[(4-piperidylidene)amino]-4,1-benzoxazepine

IIg:1,3,4,6-tetrahydro-1[(4-piperidylidene)amino]-2H-5,1-benzothiazocine

IIh: 1,3,4,6-tetrahydro-1[(4-piperidylidene)amino]-2H-5,1-benzoxazocine

SYNTHESIS Compounds of Formula I

Compounds of Formula I are prepared simply by heating, to a temperaturein the range of about 60° C. to about 200° C., a compound of formula II,preferably in the form of its hydrochloride salt, in a solvent, as shownin reaction scheme A: ##STR18## where R² is R¹, formyl, C₂ -C₄ alkanoyl,or substituted formyl or C₂ -C₄ alkanoyl, where the substituent is C₃-C₆ cycloalkyl, phenyl, phenyl substituted on adjacent carbon atoms withmethylenedioxy, or phenyl substituted with 1, 2 or 3 substituentsindividually selected from methoxy, ethoxy, bromine, chlorine, fluorine,trifluoromethyl, and C₁ -C₄ alkyl;

and X, Z, n, m, R¹, and the R's are as defined for formula I, exceptR≠OCH₃.

The solvent used in reaction (A) can be any polar solvent which is inertunder the reaction conditions. Examples of such solvents are water,lower alkanols, dimethylformamide, dimethylsulfoxide, and dioxane.Preferred is isopropanol. The preferred temperature range is 80°-90° C.The reaction can be run at subatmospheric or superatmospheric pressures,but it is preferred to operate at atmospheric pressure and the refluxtemperature of the reaction mass. The reaction involving the formulaeIIc and IId type starting materials is very fast; refluxing for fiveminutes at 80°-90° C. is usually sufficient. At lower temperatures, andwith the formulae IIa and IIb type starting materials, the reaction isslower, but a reaction time of 24 hours is sufficient in any case.

The compound of formula II will ordinarily be prepared and used inreaction (A) in the form of a salt with a mineral acid such as HCl; thecompound of formula I will then be obtained in the form of its salt withthe corresponding acid. The free base of formula I can then be obtainedsimply by treating the salt with a base such as NH₄ OH in a solvent suchas CHCl₃.

A starting material of formula II with R² other than H can be used inreaction (A) to provide the corresponding compound of formula I.However, it is usually preferred to cyclize a compound of formula IIwhere R² is H, then acylate to yield an acyl derivative, or acylate andreduce or alkylate to yield an alkyl or substituted alkyl derivativeunder conventional conditions, to provide the compounds of formula Iwhere R¹ is other than H.

The sulfones and sulfoxides of formula I can be made by oxidizing acompound of formula I where R¹ is an acyl group with an oxidizing agentwhich is conventional for such reactions. Suitable oxidizing agentsinclude hydrogen peroxide, organic peracids and sodium metaperiodate forproducing sulfoxides, and potassium permanganate for producing sulfones.Sulfones are produced in a neutral solvent such as CH₂ Cl₂ or CHCl₃ at0° to 25° C. or in glacial acetic acid at 50°-120° C. Sulfoxides areproduced in neutral solvents at reflux temperatures in the range ofabout 50°-75° C.

The sulfones and sulfoxides of formula I wherein R¹ is H can be made byhydrolysis of corresponding compounds wherein R¹ is acyl.

As stated above, compounds of formula I can be produced directly in theform of mineral acid salts. These can be converted into free bases bytreatment with bases, and the free bases can be converted into variouspharmaceutically suitable salts by reaction with appropriate acids, inconventional manner. Examples of acids which form pharmaceuticallysuitable salts with compounds of formula I are: hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric,benzoic, ascorbic, citric, pamoic, succinic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicyclic, gluconic,lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic,palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, andtoluenesulfonic acids.

Compounds of Formula II

Compounds of Formula II can be made by the series of reactions shown inreaction scheme (B): ##STR19## where X, Z, R¹, n, m, and the R's havethe meanings previously given, except R≠OCH₃.

Many of the compounds of formula V are described in the prior art. Thecompounds where m is 0 and n is 1 are prepared by reaction ofo-aminothiophenol with acrylic acid or an appropriately substitutedacrylic acid or by reaction of o-aminophenol with 3-chloropropionylchloride or a substituted 3-chloropropionyl chloride, followed bycyclization with a base such as KOH or KOC₂ H₅ in ethanol. The compoundswhere m and n are both 0 are made by reacting o-aminophenol sodium saltwith 2-chloroacetyl chloride or a substituted 2-chloroacetyl chloride orby reacting o-aminothiophenol with an alkyl bromoacetate or anappropriately substituted alkyl bromoacetate. The o-aminophenol sodiumsalt is obtained by reacting o-aminophenol with sodium hydride inbenzene or sodium ethoxide in ethanol. The reaction betweeno-aminothiophenol and the bromoacetate is carried out in the presence ofsodium ethoxide. These reactions for making compounds of formula V canbe carried out in ethanol at reflux.

Compounds of formula V wherein m is 1, n is 0 or 1, and X is sulfur canbe made by reacting a 2-nitrobenzylchloride with an α-mercaptoaceticacid (for n=0) or a β-mercaptopropionic acid (for n=1), hydrogenatingthe resulting [(2-nitrobenzyl)thio] acid, then heating the resulting[(2-aminobenzyl)thio] acid to cyclize.

Compounds of formula V wherein m is 1, n is 0 and X is oxygen are madeby reducing an aldehyde or ketone of the formula ##STR20## with sodiumborohydride to the corresponding benzyl alcohol, reacting the latterwith chloroacetyl chloride, then cyclizing with sodium ethoxide.Compounds of formula V wherein m is 1, n is 1 and X is oxygen are madeby reacting a 3-chloropropionyl chloride with a 2-aminobenzyl alcohol ina solvent such as anhydrous ether in presence of a base such astriethylamine at a temperature of 0° C. to produce a2-(chloropropionamido)benzyl alcohol, then cyclizing with sodiumethoxide.

Further information on preparation of compounds of formula V can befound in Mills et al., J. Chem. Soc., 2738 (1927), U.S. Pat. Nos.3,075,967 and 3,463,773, and French Pat. No. 1,405,271.

Conditions for reactions B(1), (2) and (3) are adequately described inthe examples which follow. A solvent such as ethanol is usually used toaid in solubility of the nitroso compound of formula III. After reactionwith the piperidone, the hydrazone of formula II is isolated as the freebase, and is then preferably converted to a salt by treatment with asolvent such as diethylether saturated with gaseous HCl.

As an alternative to reaction B(3), the nitroso compound of formula IIIcan be reduced to a hydrazine, the hydrazine isolated and then reactedwith an appropriate piperidone. These reactions are illustrated byscheme (C): ##STR21##

Reaction (C)(1) is carried out in a solvent such as ethanol. Zinc dustand acetic acid can be used as in reaction (B)(3), but other reducingmeans can also be used. For example, catalytic hydrogenation or reactionwith lithium aluminum hydride or sodiumdihydrobis(2-methoxyethanolato)aluminate can be used. After reaction(C)(1) is complete, the hydrazine of formula VI is isolated, thendissolved in ethanol saturated with gaseous HCl. Reaction (C)(2) iscarried out in this medium at reflux temperature for about 1/2 to 6hours.

Compounds of formula I substituted with methoxy on ring A can be made bythe following reaction schemes: ##STR22##

Compounds of formula I which are substituted on ring A can have one,two, or three asymmetric carbon atoms, and thus exist in stereoisomericforms. This invention includes all of the stereoisomers and mixturesthereof. Example 109 below illustrates the resolution of the racemateinto one of its optically active components.

In the following Examples, all temperatures are in degrees centigrade.

EXAMPLE 1 2,3,4,5-tetrahydro-5-nitroso-1,5-benzothiazepine

A solution of 110.4 g of sodium nitrite in 220 ml of water is addeddropwise to a well-stirred solution of 181.5 g of2,3,4,5-tetrahydrobenzothiazepine in 600 ml of glacial acetic acid,cooled in an ice-bath. After the addition is complete the mixture isstirred at room temperature for 30 minutes and then filtered. Thecrystalline solid is washed with water and air-dried. Recrystallizationfrom hexane yields 2,3,4,5-tetrahydro-5-nitroso-1,5-benzothiazepine ascream colored crystals, m.p. 85°-86°.

EXAMPLES 2-20

The following compounds are prepared by a procedure similar to thatdescribed in Example 1:

(2) 2,3,4,5-tetrahydro-2-methyl-5-nitroso-1,5-benzothiazepine, creamcolored crystals, m.p. 64°-65°

(3) 2,3,4,5-tetrahydro-3-methyl-5-nitroso-1,5-benzothiazepine, yellowliquid.

(4) 2,3,4,5-tetrahydro-2,2-dimethyl-5-nitroso-1,5-benzothiazepine, creamcolored crystals

(5) 2,3,4,5-tetrahydro-5-nitroso-2-phenyl-1,5-benzothiazepine, yellowcrystals, m.p. 112°-114°

(6)2,3,4,5-tetrahydro-5-nitroso-2-(3,4,5-trimethoxyphenyl)-1,5-benzothiazepine,cream colored crystals, m.p. 127°-129° C.

(7) 2-(p-chlorophenyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine, viscousbrown liquid

(8) 2,3-dihydro-4-nitroso-4H-1,4-benzothiazine, reddish brown liquid

(9) 1,2,3,5-tetrahydro-1-nitroso-4,1-benzothiazepine, light yellowcrystals, m.p. 88°-9°

(10) 1,3,4,6-tetrahydro-1-nitroso-2H-5,1-benzothiazocine, light yellowcrystals, m.p. 56°-58°

(11) (±)-2-ethyl-2,3,4,5-tetrahydro-5-nitroso-1,5-benzothiazepine,yellow liquid

(12) (±)-2,3,4,5-tetrahydro-5-nitroso-2-propyl-1,5-benzothiazepine,yellow liquid

(13) (±)-2,3,4,5-tetrahydro-5-nitroso-2-pentyl-1,5-benzothiazepine,yellow liquid

(14) (±)-2,3,4,5-tetrahydro-5-nitroso-2-nonyl-1,5-benzothiazepine,yellow liquid

(15) (±)-2-heptyl-2,3,4,5-tetrahydro-5-nitroso-1,5-benzothiazepine,yellow liquid

(16) (+)-3,4-dihydro-2-methyl-4-nitroso-2H-1,4-benzothiazine, yellowcrystals, m.p. 40°-41°

(17) 7-chloro-1,2,3,5-tetrahydro-1-nitroso-4,1-benzothiazepine

(18) 8-chloro-1,3,4,6-tetrahydro-2H-5,1-benzothiazocine

(19) 1,2,3,4-tetrahydro-7-methyl-5-nitroso-1,5-benzothiazepine

(20) 2,3-dihydro-6-methyl-4-nitroso-4H-1,4-benzothiazine

EXAMPLE 212,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride

Glacial acetic acid (700 ml) is added dropwise to a vigorously stirredmixture of 62 g of 2,3,4,5-tetrahydro-5-nitroso-1,5-benzothiazepine, 49g of 4-piperidone hydrochloride monohydrate, 400 ml of anhydrousethanol, and 140 g of zinc dust, cooled in an ice-bath. After theaddition is complete, the mixture is stirred at room temperature for 1hr. and filtered. The residue is washed with a small quantity of ethanoland the combined filtrates heated at 65°-70° C. for 1 hour and thenstripped of ethanol and acetic acid under reduced pressure. The residualviscous liquid is dissolved in minimum quantity of water and added withstirring, to excess of well-cooled 25% aqueous sodium hydroxide. Themixture is thoroughly extracted with chloroform and the combinedchloroform extract washed well with water, dried over anhydrousmagnesium sulfate and stripped of the solvent under reduced pressure.The residue on trituration with ether and cooling yields2,3,4,5-tetrahydro-5-[(4-piperidylidene)amino]-1,5-benzothiazepine ascream colored crystals, m.p. 113°-115°. A sample of this hydrazone meltsat 115°-117° C. after recrystallization from a mixture of benzene andhexane.

The aforementioned hydrazone is converted into its hydrochloride bydissolving it in anhydrous tetrahydrofuran and adding the solution, withstirring, to an excess of anhydrous ether saturated with gaseoushydrogen chloride. A solution-suspension of 25 g of the hydrochloridethus obtained in 500 ml isopropanol is refluxed for 4 hours, cooled inan ice-bath and filtered. The solid is washed with anhydrous ether andrecrystallized from a large quantity of anhydrous ethanol to yield2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 293°-295° (dec.), as colorless crystals. Thecorresponding lactate and acetate, both salts being better than 10%soluble in water, melt at 173°-175° and 129°-130°, respectively.

EXAMPLES 22-59

The following compounds are prepared by a procedure similar to thatdescribed in Example 9:

(22)(±)-2,3,8,9,10,11-hexahydro-3-phenyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 276°-278° (dec.)

(23)(±)-3-(p-chlorophenyl)-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinemethanesulfonate, m.p. 206°-207° (dec.)

(24)(±)-2,3,8,9,10,11-hexahydro-3-(3,4,5-trimethoxyphenyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 284°-285° (dec.)

(25)(±)-2,3,8,9,10,11-hexahydro-2-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 276°-277° (dec.)

(26)(±)-2,3,8,9,10,11-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 276°-278° (dec.)

(27)2,3,8,9,10,11-hexahydro-3,3-dimethyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 298°-300° (dec.)

(28)1,2,7,8,9,10-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazinehydrochloride, m.p. 290°-292° (dec.)

(29)2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine-9-carboxylicacid ethyl ester, m.p. 168°-170° (dec.)

(30)2,3,8,9,10,11-hexahydro-9-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 268°-270° (dec.)

(31)9-(cyclopropylmethyl)-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 256°-258° (dec.)

(32)9-benzyl-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 265°-267° (dec.)

(33)2,3,8,9,10,11-hexahydro-9-phenethyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5benzothiazepinehydrochloride, m.p. 260°-262° (dec.)

(34)(±)-2,3,8,9,10,11-hexahydro-9-phenethyl-3-phenyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinemethanesulfonate, m.p. 193°-195°

(35)1,2,7,8,9,10-hexahydro-8-phenethylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazinehydrochloride, m.p. 265°-267° (dec.)

(36)9-butyl-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 260°-262° (dec.)

(37)9-cyclopropyl-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 248°-250° (dec.)

(38)1,2,7,8,9,10-hexahydro-8-methylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazinehydrochloride, m.p. 270°-272° (dec.)

(39)1,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzothiazepinehydrochloride, off-white crystals, m.p. 277°-278° (dec.)

(40)2,3,9,10,11,12-hexahydro-1H,5H-pyrido[3',4':4,5]pyrrolo[3,2,1-kl][5,1]benzothiazocinehydrochloride, colorless crystals, m.p. 260°-262° (dec.)

(41)(±)-9-cyclopropyl-2,3,8,9,10,11-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 248°-250° (dec.)

(42)(±)-2,3,8,9,10,11-hexahydro-3-propyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless, shiny crystals, m.p. 275°-277° (dec.)

(43)8-cyclopropyl-1,2,7,8,9,10-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazinehydrochloride, colorless crystals, m.p. 238°-240°

(44)(±)-3-ethyl-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 263°-265° (dec.)

(45)(±)-2,3,8,9,10,11-hexahydro-3-nonyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 268°-270° (dec.)

(46)(±)-8-cyclopropyl-1,2,7,8,9,10-hexahydro-2-methylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazinehydrochloride, colorless crystals, m.p. 268°-270° (dec.)

(47)(±)-2,3,8,9,10,11-hexahydro-3-pentyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 273°-275° (dec.)

(48)(±)-9-cyclopropyl-2,3,8,9,10,11-hexahydro-3-pentyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 240°-242° (dec.)

(49)(±)-9-(cyclopropylmethyl)-2,3,8,9,10,11-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 248°-249° (dec.)

(50)8-(cyclopropylmethyl)-1,2,7,8,9,10-hexahydropyrido-[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazinehydrochloride, off-white crystals, m.p. 255°-256° (dec.)

(51)(±)-3-heptyl-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless powder, m.p. 278°-280° (dec.)

(52)(±)-2,3,8,9,10,11-hexahydro-3,9-dimethyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 256°-257° (dec.)

(53)(±)-9-benzyl-2,3,8,9,10,11-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, colorless crystals, m.p. 255°-257°

(54)6-chloro-1,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzothiazepinehydrochloride

(55)6-chloro-9-cyclopropyl-1,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzothiazepinehydrochloride

(56)7-chloro-2,3,9,10,11,12-hexahydro-1H,5H-pyrido[3',4':4,5]pyrrolo[3,2,1-kl][5,1]benzothiazocinehydrochloride

(57)7-chloro-2,3,9,10,11,12-hexahydro-10-methyl-1H,5H-pyrido[3',4':4,5]pyrrolo[3,2,1-kl][5,1]benzothiazocinehydrochloride

(58)2,3,8,9,10,11-hexahydro-6-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride

(59)8-cyclopropyl-1,2,7,8,9,10-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazinehydrochloride

EXAMPLE 609-allyl-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride

Allyl bromide (2.4 g) is added, in one lot, to a stirred mixture of2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine(4.9 g), absolute ethanol (50 ml) and powdered anhydrous sodiumcarbonate (5 g) and the mixture refluxed for 2 hours, stirring beingcontinued. It is then cooled and poured into excess of ice and water andthe sticky semi-solid that separates is extracted with chloroform andthe chloroform extract is washed with water, dried over anhydrousmagnesium sulfate and stripped of the solvent under reduced pressure.The residue is dissolved in requisite quantity of anhydrous ether andadded to excess of anhydrous ether saturated with gaseous hydrogenchloride. The solid that separates is filtered, washed with anhydrousether and recrystallized from isopropyl alcohol and anhydrous ether toyield9-allyl-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 235°-236° (dec.)

EXAMPLE 612,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

Trifluoroacetic anhydride (19.7 g) is added in one lot, to awell-cooled, stirred solution of2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiaazepine(15.1 g) in anhydrous pyridine (50 ml) and the resulting mixture isstirred at room temperature for 30 minutes and then poured into excessof ice and water containing 75 ml of concentrated hydrochloric acid. Thesolid that separates is filtered, washed with water, air-dried andrecrystallized from tetrahydrofuran-pentane to yield2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine,m.p. 140°-142°.

EXAMPLE 622,3,8,9,10,11-hexahydro-9-(3,4,5-trimethoxybenzyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

A solution of 2.3 g of 3,4,5-trimethoxybenzoyl chloride in 25 ml ofCHCl₃ is added, dropwise, to a vigorously stirred mixture of a solutionof 2.3 g of2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinein 50 ml of chloroform and 50 ml of a saturated solution of sodiumcarbonate in water. After the addition is complete the mixture isstirred for an additional 15 minutes and the chloroform layer separated,washed successively with water, 2 N hydrochloric acid and water, driedover anhydrous magnesium sulfate and stripped of the solvent. Theresidual viscous liquid is triturated with ether and the solid thusobtained is filtered and recrystallized from tetrahydrofuran and hexaneto yield2,3,8,9,10,11-hexahydro-9-(3,4,5-trimethoxybenzoyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine,m.p. 183°-185°. Reduction by the method of Example 64 yields the titlecompound.

EXAMPLE 63 9-[2-(3,4-dimethoxyphenyl)acetyl]-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

A solution of 8 g of dicyclohexylcarbodiimide in 50 ml of chloroform isadded, in one lot, to a stirred solution of 9.2 g of2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepineand 7.6 g of (3,4-dimethoxyphenyl)acetic acid in 250 ml of chloroform.The mixture is then stirred for 1 hour and filtered and the filtratestripped of the solvent under reduced pressure. The residual viscousliquid is triturated with ethanol and the solid thus obtained isfiltered and recrystallized from ethanol to yield9-[2-(3,4-dimethoxyphenyl)acetyl]-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine,m.p. 232°-233°.

EXAMPLE 649-(3,4-dimethoxyphenethyl)-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride

Ten grams of a 75% benzene solution of sodiumdihydrobis(2-methoxyethanolato)aluminate is added dropwise to a stirredsolution-suspension of 4.1 g of9-[2-(3,4-dimethoxyphenyl)acetyl]-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinein 100 ml of anhydrous benzene. After the addition is complete themixture is stirred and refluxed for 2 hours, cooled in an ice-bath andtreated with 20 ml of 20% aqueous sodium hydroxide added dropwiseinitially and rapidly subsequently. The mixture is then diluted with 200ml of water, the benzene layer separated, and the aqueous layer isextracted thrice with chloroform. The benzene and chloroform extractsare washed with water, combined, dried over anhydrous magnesium sulfateand stripped of the solvent under reduced pressure. The residual viscousliquid is dissolved in requisite quantity of anhydrous tetrahydrofuranand added to an excess of anhydrous ether saturated with gaseoushydrogen chloride. The solid thus obtained is filtered, washed well withanhydrous ether and recrystallized from ethanol, to yield9-(3,4-dimethoxyphenethyl)-2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine hydrochloride,m.p. 253°-255°(dec.).

EXAMPLE 652,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinemethanesulfonate

A solution of 5 g of2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinein 50 ml of anhydrous tetrahydrofuran is added in one lot, withagitation, to a solution of 2.5 g of methanesulfonic acid in 50 ml ofanhydrous tetrahydrofuran. Immediate precipitation of the salt occursand the mixture is cooled, filtered, and the solid washed with anhydroustetrahydrofuran followed by anhydrous ether. It is recrystallized from amixture of isopropanol and ethanol to yield2,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinemethanesulfonate, m.p. 225°-226°(dec.).

EXAMPLE 662,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine4-oxide methanesulfonate

A solution of m-chloroperbenzoic acid (3.2 g of approximately 85% purematerial) in 100 ml of CH₂ Cl₂ is added in one lot to a stirred solutionof2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine(5.1 g) in 150 ml of CH₂ Cl₂ cooled to -20°. The mixture is stirred at-20° for 15 minutes and then extracted with 100 ml of aqueous sodiumbicarbonate (saturated solution). The CH₂ Cl₂ is separated, washed withwater, dried over anhydrous magnesium sulfate and stripped of thesolvent in vacuo. The residual viscous liquid is triturated withanhydrous ether and the mixture is evaporated to remove the ether. Theresidue is taken up in 50 ml of ethanol, treated with 8 ml of 10% NaOH,refluxed for 1 hour and cooled. Most of the ethanol from the mixture isremoved under reduced pressure and the residue diluted with 200 ml ofwater and extracted twice with chloroform. The combined chloroformlayers are washed thoroughly with water, dried over anhydrous magnesiumsulfate and stripped of the solvent under reduced pressure. The residualheavy viscous liquid is dissolved in 50 ml of anhydrous THF and added toa solution of 2.8 g of CH₃ SO₃ H in anhydrous THF with swirling. Thesolid that separates is filtered, washed with THF and then with etherand recrystallized from a mixture of isopropanolethanol-anhydrous ether,m.p. 241°-242°(dec.).

EXAMPLE 67(±)-3-chloro-2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

A solution of sulfuryl chloride (3.9 g) in chloroform (10 ml) is addeddropwise to a stirred solution of2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine(10.2 g) in anhydrous benzene (240 ml). After the addition is complete,the mixture is stirred at room temperature for 30 minutes and strippedof the solvents under reduced pressure and the residue recrystallizedfrom a mixture of tetrahydrofuran and pentane to yield(±)-3-chloro-2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine,m.p. 133°-134°.

EXAMPLES 68-80

By substituting the proper starting material in Example 67, thefollowing compounds can be prepared similarly:

(68)(±)-3-chloro-2,3,8,9,10,11-hexahydro-3-methyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(69)(±)-3-chloro-2,3,8,9,10,11-hexahydro-2-methyl-9(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3ef][1,5]benzothiazepine

(70)(±)-3-chloro-2,3,8,9,10,11-hexahydro-3-propyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzotiazepine

(71)(±)-3-chloro-2,3,8,9,10,11-hexahydro-3-pentyl-9-(trisfluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(72)(±)-3-chloro-2,3,8,9,10,11-hexahydro-3-nonyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(73)(±)-3-chloro-2,3,8,9,10,11-hexahydro-3-phenyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(74)(±)-3-chloro-3-ethyl-2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(75)(±)-3-chloro-3-heptyl-2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(76)(±)-3-chloro-3-(p-chlorophenyl)-2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(77)(±)-3-chloro-3-(3,4-dimethoxyphenyl)-2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(78)(±)-3-chloro-3-cyclohexyl-2,3,8,9,10-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(79)(±)-2-chloro-1,2,7,8,9,10-hexahydro-2-methyl-8-(trifluoroacetyl)pyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazine

(80)(±)-2-chloro-1,2,7,8,9,10-hexahydro-8-(trifluoroacetyl)pyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazine

EXAMPLE 81(±)-2,3,8,9,10,11-hexahydro-3-methoxy-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

A mixture of(±)-3-chloro-2,3,8,9,10,11-hexahydro-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine(5.5 g) and methanol (75 ml) is refluxed on a steam bath for 30 minutesand then stripped of the solvent under pressure. The residue isrecrystallized from isopropanol to yield(±)-2,3,8,9,10,11-hexahydro-3-methoxy-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine,m.p. 155°-156°.

EXAMPLES 82-94

By substituting the compounds of Examples 68-80 as starting materials inthe procedure of Example 81, the following compounds can be prepared:

(82)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-methyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(83)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-2-methyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(84)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-propyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(85)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-pentyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(86)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-nonyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(87)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-phenyl-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(88)(±)-3-ethyl-2,3,8,9,10,11-hexahydro-3-methoxy-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(89)(±)-3-heptyl-2,3,8,9,10,11-hexahydro-3-methoxy-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(90)(±)-3-(p-chlorophenyl)-2,3,8,9,10,11-hexahydro-3-methoxy9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(91)(±)-3,4-dimethoxyphenyl-2,3,8,9,10,11-hexahydro-3-methoxy-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(92)(±)-3-cyclohexyl-2,3,8,9,10,11-hexahydro-3-methoxy-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef-[1,5]benzothiazepine

(93)(±)-1,2,7,8,9,10-hexahydro-2-methoxy-2-methyl-8-(trifluoroacetyl)pyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazine

(94)(±)-1,2,7,8,9,10-hexahydro-2-methoxy-8-(trifluoroacetyl)pyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazine

EXAMPLE 95(±)-2,3,8,9,10,11-hexahydro-3-methoxy-1H-pyrido[3'4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinemaleate (1:1)

A mixture of(±)-2,3,8,9,10,11-hexahydro-3-methoxy-9-(trifluoroacetyl)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine(4.8 g), ethanol (50 ml) and 5% aqueous sodium hydroxide (10 ml) isrefluxed for 1 hour and then stripped of most of the ethanol underreduced pressure. The residue is treated with water and extracted withether. The ether extract is washed with water, dried over anhydrousmagnesium sulfate and stripped of the solvent under reduced pressure.The residual viscous liquid is dissolved in a minimum quantity ofanhydrous ether and added to a solution of maleic acid (1.6 g) inrequisite quantity of anhydrous ether. The solid that separates isfiltered, washed with ether and recrystallized from isopropanol to yield(±)-2,3,8,9,10,11-hexahydro-3-methoxy-1H-pyrido[3'4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinemaleate, m.p. 165°-166°.

EXAMPLES 96-108

By substituting the compounds of Examples 82-94 as starting materials inthe procedure of Example 95, then converting the maleate salts to thefree bases, the following compounds can be prepared:

(96)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(97)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-2-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(98)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-propyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(99)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-pentyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(100)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-nonyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(101)(±)-2,3,8,9,10,11-hexahydro-3-methoxy-3-phenyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(102)(±)-3-ethyl-2,3,8,9,10,11-hexahydro-3-methoxy-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(103)(±)-3-heptyl-2,3,8,9,10,11-hexahydro-3-methoxy-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(104)(±)-3-(p-chlorophenyl)-2,3,8,9,10,11-hexahydro-3-methoxy-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(105)(±)-3-(3,4-dimethoxyphenyl)-2,3,8,9,10,11-hexahydro-3-methoxy-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(106)(±)-3-cyclohexyl-2,3,8,9,10,11-hexahydro-3-methoxy-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine

(107)(±)-1,2,7,8,9,10-hexahydro-2-methoxy-2-methyl-pyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazine

(108)(±)-1,2,7,8,9,10-hexahydro-2-methoxypyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzothiazine

EXAMPLE 109(±)-2,3,8,9,10,11-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride

(±)-2,3,8,9,10,11-Hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride is converted to its base by treatment with ammoniumhydroxide, extraction with CHCl₃, evaporation of the solvent andrecrystallization of the residue from hexane, m.p. 110°-112°. A solutionof this base (8.6 g) in anhydrous tetrahydrofuran (30 ml) is added to asolution of (-)-2,3:3,6-di-O-isopropylidene-2-keto-L-gulonic acidhydrate ([α]_(D) ²⁵ =-21.3° (2% in methanol) (9.8 g) in anhydroustetrahydrofuran (100 ml), with agitation. After 15 minutes the mixtureis stripped of the solvent under reduced pressure and the viscous,syrupy residue is triturated with isopropanol whereupon it solidifies.The solid is filtered and recrystallized from isopropanol untilsuccessive specific rotations are close. (After four recrystallizations[α]_(D) ²⁷ =-63.81), m.p. 125°-127° (foaming). The free base isliberated from the salt with ammonium hydroxide, isolated by extractionwith CHCl₃ and converted to its hydrochloride by dissolution inanhydrous tetrahydrofuran and addition to excess of anhydrous ethersaturated with gaseous hydrogen chloride. Recrystallization frommethanol yields(+)-2,3,8,9,10,11-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinehydrochloride, m.p. 276°-278° (dec.), [α]_(D) ²⁷ =+8.30 (c 2% inmethanol).

EXAMPLE 1101,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepinehydrochloride

1,2,3,5-Tetrahydro-4,1-benzoxazepine, prepared according to E. Testa andL. Fontanella, Fr. Pat. No. 1,405,271, is converted to the corresponding5-nitroso derivative as described in Example 1 obtained as yellowcrystals, m.p. 62°-64° C. The latter, 8.3 g, is dissolved in 130 ml ofmethanol. To the resulting solution, cooled to 10°-15° C. there is added20 g of Zn dust in small portions along with 25 ml of acetic acid, addeddropwise. After the addition is complete, the mixture is stirred at roomtemperature for 3 hours and then filtered. The filtrate is stripped ofthe solvent under reduced pressure and the oily residue is treated with5 N HCl to yield 1-amino-1,2,3,5-tetrahydro4,1-benzoxazepinehydrochloride, which is filtered and washed on the filter with ether,m.p. 229°-230°. The aforementioned hydrazine hydrochloride (3 g.) isreacted with 2.6 g of 4-piperidone hydrochloride in 30 ml of ethanolsaturated with gaseous HCl by heating to reflux for 2 hours. The HClsalt of1,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepineseparates out in the course of the reaction. The product was cooled,filtered, and recrystallized from ethanol. Melting point of theresulting product was 296°-297°.

EXAMPLE 1111,2,8,9,10,11-hexahydro-9-methyl-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepinehydrochloride

By a procedure similar to that described in Example110,1-amino-1,2,3,5-tetrahydro-4,1-benzoxazepine hydrochloride isreacted with 1-methyl-4-piperidone to yield the title compound, m.p.286°-288°.

EXAMPLE 112(±)-1,2,8,9,10,11-hexahydro-4-phenyl-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepinehydrochloride

1-Amino-1,2,3,5-tetrahydro-5-phenyl-4,1-benzoxazepine [Testa andFontanella, I1 Farmaco, 18, 815 (1963)] is reacted with 4-piperidonehydrochloride as described in Example 110 to yield the title compound,m.p. 297°-299°.

EXAMPLE 1136-chloro-1,2,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepinehydrochloride

By the procedure described in Example 1, the appropriate benzoxazepineis converted to 7-chloro-1,2,3,5-tetrahydro-1-nitroso-4,1-benzoxazepine,m.p. 54°-56°. The latter is reduced to the corresponding 1-aminoderivative hydrochloride, which is reacted with 4-piperidonehydrochloride to yield the title compound, m.p. 304°-305°.

EXAMPLE 1141,2,8,9,10,11-hexahydro-6-methyl-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepinehydrochloride

In a manner analogous to the preparation of1,2,3,5-tetrahydro-4,1-benzoxazepine (E. Testa and L. Fontanella, Fr.Pat. No. 1,405,271), 5-methylanthranilic acid is converted to1,2,3,5-tetrahydro-7-methyl-4,1-benzoxazepine, m.p. 102°, which, by aprocedure similar to that described in Example 110, is converted to thetitle compound, m.p. 320° (dec).

EXAMPLE 115(±)-1,2,8,9,10,11-hexahydro-4-methyl-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepinehydrochloride

According to the procedure described in Example 1, the appropriatebenzoxazepine is converted to1-amino-1,2,3,5-tetrahydro-5-methyl-4,1-benzoxazepine hydrochloride,m.p. 198°-200°, which is reacted with 4-piperidone hydrochloride toyield the title compound, m.p. 285°-286° (dec.).

EXAMPLE 1162,3,9,10,11,12-hexahydro-1H,5H-pyrido[3',4':4,5]pyrrolo[3,2,1-kl][5,1]benzoxazocinehydrochloride

A solution of 2.54 g of β-chloropropionyl chloride in 30 ml of anhydrousether is added slowly to a stirred solution of 2.13 g of 2-aminobenzylalcohol in 100 ml of anhydrous ether and 1.8 ml of triethylaminepreviously cooled to 0° C. After the addition is complete, stirring iscontinued for another hour, keeping the reaction mixture at 0° C. Water(30 ml.) is then added, and the reaction mixture is acidified withhydrochloric acid. The ether layer is separated, washed with an aqueoussaturated solution of sodium chloride, dried with sodium sulfate,filtered and evaporated to dryness. The resulting2-(2-chloropropionamido)benzyl alcohol is converted, in a manner similarto that described for the preparation of1,2,3,5-tetrahydro-4,1-benzoxazepine (E. Testa and L. Fontanella, Fr.Pat. No. 1,405,271) to 1,3,4,6-tetrahydro-2H-5,1-benzoxazocine. Thelatter, by a procedure similar to that described in Example 110 isconverted to the title compound.

EXAMPLE 1171,2,7,8,9,10-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

Chloroacetyl chloride (104 g) is added slowly to a stirred mixture ofo-aminophenol (96 g), sodium bicarbonate (100 g) and chloroform (1400ml). After the addition is complete the reaction mixture is stirred atroom temperature for 2 hours. The resulting chloroacetamide derivative,which separates in the course of the reaction, is filtered and addedwith stirring to 1 liter of NaOH, producing 2H-1,4-benzoxazin-3(4H)-one,which is filtered and washed with H₂ O, m.p. 169°-170°. The latter (30g) is added portionwise to a suspension of 26 g of LiAlH₄ in 1500 ml ofanhydrous ether, keeping the temperature at 10° during the addition.After the addition is complete the reaction mixture is heated to refluxfor 2 hours. It is then cooled, decomposed with water and filtered. Theorganic layer is separated and dried over anhydrous sodium sulfate; thesolvent is removed in the rotary evaporator and the oily productobtained distilled to yield 3,4-dihydro-2H-1,4 -benzoxazine (b₇₆₀265°-267°). In a like manner as in Example 1, the latter benzoxazine isconverted to the corresponding 4-nitroso derivative, which is worked upas described in Example 110 to give4-amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride [m.p. 160° (dec.)]and finally the title compound m.p. 255° (dec.).

EXAMPLE 1181,2,7,8,9,10-hexahydro-8-methylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

By a procedure similar to Example 110,4-amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride is reacted with1-methyl-4-piperidone to yield the title compound, m.p. 245°-246°.

EXAMPLE 1198-cyclopropyl-1,2,7,8,9,10-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

4-Amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride is reacted with1-cyclopropyl-4-piperidone according to the procedure of Example 110 toyield the title compound, m.p. 232°-233°.

EXAMPLE 1201,2,7,8,9,10-hexahydro-5-methylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

Starting with 2-amino-5-methylphenol and following the procedure ofExample 117, 4-amino-3,4-dihydro-7-methyl-2H-1,4-benzoxazinehydrochloride is obtained, m.p. 148° (dec.), which is reacted with4-piperidone hydrochloride to yield the title compound, m.p. 300°(dec.).

EXAMPLE 1211,2,7,8,9,10-hexahydro-5,8-dimethylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

4-Amino-3,4-dihydro-7-methyl-2H-1,4-benzoxazine hydrochloride is reactedwith 1-methyl-4-piperidone according to the procedure of Example 110 toyield the title compound, m.p. 248°-249°.

EXAMPLE 1221,2,7,8,9,10-hexahydro-6-methylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

Starting with 2-amino-4-methylphenol and following the procedure ofExample 117, 4-amino-3,4-dihydro-6-methyl-2H-1,4-benzoxazinehydrochloride is obtained, m.p. 153°-155° (dec.), which is reacted with4-piperidone hydrochloride to yield the title compound, m.p. 328°-329°(dec.).

EXAMPLE 123(±)-1,2,7,8,9,10-hexahydro-2-phenylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

By a procedure similar to that described for the synthesis of3,4-dihydro-2H-1,4-benzoxazine (Example 142), o-aminophenol and2-chlorophenylacetyl chloride produces3,4-dihydro-2-phenyl-2H-1,4-benzoxazine, m.p. 113°-116° which, accordingto the reaction scheme of Example 110 is converted to the titlecompound, m.p. 311°-313°.

EXAMPLE 124(±)-1,2,7,8,9,10-hexahydro-8-methyl-2-phenylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazinehydrochloride

By the reaction scheme described in Example 110,3,4-dihydro-2-phenyl-2H-1,4-benzoxazine is converted to thecorresponding 4-amino derivative which is reacted with1-methyl-4-piperidone to give the title compound, m.p. 274°-276°.

EXAMPLE 1252,3,8,9,10,11-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzoxazepinehydrochloride

By a procedure similar to that described in Example 12,3,4,5-tetrahydro-1,5-benzoxazepine [G. S. Sidhu et al. Indian J. Chem.2, 211 (1964)] is converted to the corresponding 5-nitroso derivative.The latter, which separates as a heavy oil, is converted, according tothe reaction scheme described in Example 110, to5-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine hydrochloride, m.p.192°-194° which is reacted with 4-piperidone to yield the titlecompound, m.p. 283°-285° (dec.).

EXAMPLES 126-129

By the procedure of Example 125, the following compounds can beprepared, starting from 2,3,4,5-tetrahydro-8-methyl-1,5-benzoxazepine:

(126) 2,3,4,5-tetrahydro-8-methyl-5-nitroso-1,5-benzoxazepine

(127) 5-amino-2,3,4,5-tetrahydro-8-methyl-1,5-benzoxazepine

(128)2,3,4,5-tetrahydro-8-methyl-5-[(4-piperidylidene)amino]1,5-benzoxazepine

(129)2,3,8,9,10,11-hexahydro-6-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzoxazepine

EXAMPLES 130-133

By the procedure of Example 125, the following compounds can beprepared, starting from 3,4-dihydro-8-methyl-2H-1,4-benzoxazine:

(130) 3,4-dihydro-8-methyl-4-nitroso-2H-1,4-benzoxazine

(131) 4-amino-3,4-dihydro-8-methyl-2H-1,4-benzoxazine

(132) 3,4-dihydro-8-methyl-4[(4-piperidylidene)amino]1,4-benzoxazine

(133)1,2,7,8,9,10-hexahydro-4-methylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazine

EXAMPLES 134-137

By the procedure of Example 125, the following compounds can be madestarting from 3,4-dihydro-2-isopropyl-2H-1,4-benzoxazine:

(134) 3,4-dihydro-2-isopropyl-4-nitroso-2H-1,4-benzoxazine

(135) 4-amino-3,4-dihydro-2-isopropyl-2H-1,4-benzoxazine

(136) 3,4-dihydro-2-isopropyl-4[(4-piperidylidene)amino]1,4-benzoxazine

(137)1,2,7,8,9,10-hexahydro-2-isopropylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazine

EXAMPLES 138-140

By reacting the compounds of Examples 127, 131, and 135 with1-methyl-4-piperidone to provide the corresponding compounds of formulaII, then cyclizing according to reaction scheme A, the followingcompounds can be prepared:

(138)2,3,8,9,10,11-hexahydro-6,9-dimethyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzoxazepine

(139)1,2,7,8,9,10-hexahydro-4,8-dimethylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazine

(140)1,2,7,8,9,10-hexahydro-2-isopropyl-8-methylpyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazine

The drugs of this invention can be administered in the usualpharmaceutical dosage forms, such as tablets, capsules, syrups, elixirs,suspensions, injectables, implants, suppositories etc. Such compositionscan be described broadly as consisting essentially of a compound offormula I or salt thereof and one or more pharmaceutically acceptablevehicles or excipients. (The expression "consisting essentially of" isused to indicate that in addition to the ingredients specificallyrecited, i.e. the essential ingredients, the compositions can containother ingredients, provided they do not interfere with the intended useof the compositions.) The compositions and/or method of preparation maybe designed to meet the requirements of the intended dosage form.

The concentration of the active ingredient and the pharmaceuticalcarrier may vary for each dosage form. The ordinary range for tabletsand capsules is 10-90% by weight of the active ingredient and 90-10% ofthe carrier. For the liquid dosage forms such as such as syrups,suspensions and injections, the concentration is ordinarily between 0.1and 10% by weight of active ingredient and corresponding, 99.9-90% ofthe vehicle.

Doses of active ingredient between about 0.1 and 100 mg/kg/day can beused to induce sedation. The preferred range is 1 to 30 mg/kg/day. Forthose compounds which are anti-depressants, similar doses can be used tocombat depression. The daily dosage can be given all at once or inintervals of from 3 to 6 hours.

Typical formulations of the type listed above which may be used for theadministration of these compounds are:

EXAMPLE A

    ______________________________________                                        Ingredient             mg./tablet                                             ______________________________________                                        compound of Example 21 15 mg.                                                 lactose, USP           183 mg.                                                magnesium stearate, USP                                                                              2 mg.                                                  color (if desired)     q.s.                                                   ______________________________________                                    

All of the above ingredients are passed through a suitable sieve,blended for 20 minutes, and compressed directly into tablets of 200 mg.on a suitable tablet press using a 11/32" punch and die.

EXAMPLE B

    ______________________________________                                        Ingredients            mg./capsule                                            ______________________________________                                        compound of Example 37 25 mg.                                                 lactose, USP           100 mg.                                                magnesium stearate, USP                                                                              1 mg.                                                  colloidal silicon dioxide, N.F.                                                                      2 mg.                                                  ______________________________________                                    

The combined ingredients are blended and passed through a 40 mesh sieve,and the mixture is encapsulated into a two-piece hard gelatin No. 3capsule on a suitable encapsulating machine at a net weight of 128 mg.

EXAMPLE C

    ______________________________________                                        Ingredients              gram/liter                                           ______________________________________                                        Compound of Example 59   10 g.                                                propylparaben, USP       0.2 g.                                               methylparaben, USP       1.8 g.                                               sodium carboxymethylcellulose, USP (CMC)                                                               5 g.                                                 polysorbate 80, USP      1 g.                                                 Water for Injection      q.s. to 1 liter                                      ______________________________________                                    

The parabens, CMC and one-half of the polysorbate 80 are dissolved inabout 700 ml. of Water for Injection, with agitation at 80° (solutionA). A slurry is made of the active ingredient, one-half of thepolysorbate 80 and about 200 ml. of Water for Injection (slurry B).Solution A is aseptically filtered through a Millipore filter to renderit sterile, while slurry B is autoclaved for 30 minutes at 15 lbs. steampressure to make it sterile. A and B are aseptically combined, broughtto correct volume with sterile Water for Injection, and mixed tohomogeneity.

The sedative effect of compounds of this invention is shown in thefollowing tests:

"M.E.D."

Results given in: mg/kg po/mouse Mouse Screen: The minimal effectivedose (MED) is the lowest oral dose producing an obvious decrease inlocomotor activity, using observational techniques. Groups of 3 mice aregiven decreasing oral doses at 0.5 log intervals (300, 100, 30 . . .etc.) until no behavioral effects are evident. Decrease of locomotoractivity is indicative of general central nervous system depressantactivity.

"ED₅₀ "

Results given in: mg/kg po/mouse Mouse Locomotor Activity Test: The ED₅₀is the dose causing a 50% decrease in activity compared to animals givensaline as controls. Photocell-activated cages are used to record thelocomotor activity of groups of 5 animals. The mice are placed in theactophotometers 30 minutes after oral administration of saline or testcompound, and locomotor activity is recorded for 1 hour. This test givesa more precise evaluation than the screen described above.

Results in these tests for some compounds of this invention and astandard (flurazepam) are shown in the following table.

    ______________________________________                                        Compound of                                                                   Example    Salt        M.E.D.      ED.sub.50                                  ______________________________________                                        flurazepam             10          7                                          21         HCl         10          --                                         21         lactate     10          --                                         21 (65)    mesylate    10          8                                          21         acetate     10          7                                          21         --          3           6                                          22         HCl         100         94                                         23         mesylate    30          >100                                       24         HCl         30          >100                                       26         "           3           3                                          27         "           10          50                                         28         "           10          --                                         30         "           30          12                                         60         "           10          --                                         36         "           10          44                                         37         "           10          24                                         31         "           30          28                                         32         "           10          23                                         33         "           10          >100                                       35         "           10          >100                                       34         mesylate    300         --                                         25         HCl         10          23                                         38         "           30          >100                                       61         --          3           88                                         29         --          >300        --                                         66         mesylate    10          >100                                       64         HCl         10                                                     81         --          >300                                                   41         HCl         10                                                     42         "           10                                                     95         maleate     10                                                     109 (+)-isomer                                                                           HCl         3                                                      44         "           30                                                     45         "           3                                                      47         "           100                                                    48         "           >300                                                   49         "           3                                                      51         "           100                                                    52         "           30                                                     40         "           1                                                      43         "           30                                                     46         "           100                                                    50         "           10                                                     117        "           10                                                     118        "           30                                                     119        "           30                                                     123        "           10                                                     124        "           100                                                    120        "           1                                                      121        "           100                                                    122        "           100                                                    110        "           10                                                     111        "           30                                                     112        "           10                                                     113        HCl         3                                                      114        "           10                                                     115        "           3                                                      125        "           30                                                     39         "           1                                                      ______________________________________                                    

Some of the compounds have antidepressant activity as well assedative-hypnotic activity, as shown in the tetrabenazine (TBZ)antagonism test, or "anti-TBZ" test. The anti-TBZ test is a standardprocedure for the detection of potential antidepressant agents.

"ED₅₀ - Ptosis" Results given in mg/kg. po/mouse Anti-TBZ Test

Groups of 5 to 10 mice are given graded oral doses of a test compound.One hour after drug administration, the mice are given a subcutaneousdose of 40 mg/kg TBZ (as the mesylate). Thirty minutes after TBZadministration, each mouse is placed in the center of a circle, thediameter of which is twice the length of the mouse. Thirty seconds afterthe mouse is placed in the circle, two sets of readings are taken. Theability of the mouse to move out of the circle is noted and the degreeof ptosis (eyelid closure) is rated on a subjective scoring system.Compounds of the imipramine type tend to reverse only the ptosis inducedby TBZ. Compounds with monoamine oxidase inhibitory activity andamphetamine-like activity have been found to antagonize the ptosis andimmobility induced by TBZ.

Results for compounds of this invention which have been found active inthe anti-TBZ test are as follows:

    ______________________________________                                        Compound of                                                                   Example         Salt       ED.sub.50 -Ptosis                                  ______________________________________                                        Imipramine                 2                                                  28              HCl        20                                                 37              "          6                                                  41              "          6                                                  43              "          2                                                  50              "          20                                                 117             "          4.8                                                119             "          2                                                  120             "          25                                                 121             "          20                                                 ______________________________________                                    

Some of the compounds of this invention, especially thehexahydro-3-substituted-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepinesin which there is no substituent on the 9-position, are antibacterial,as determined in the standard microbiological test tube liquid serialdilution method.*

Microbiological Test

Ten mg of each compound are mixed with 50 ml of sterile distilled watercontaining 2.0 ml of dimethylformamide and one drop of Tween 80.Appropriate dilutions are made from this solution in sterile distilledwater.

Test compound concentrations are made by mixing 1.0 ml of a dilutedsolution with 1.0 ml of sterile double-strength Bacto brainheartinfusion broth** in plugged test tubes.

The final test concentrations of 100 μg, 50 μg, 10 μg, 2 μg and 0.4 μgof compound per ml of culture medium are aseptically inoculated with twodrops of an overnight broth culture of a test bacterium and incubated at37° C.

After incubation for 48 hours, the test tubes are observed for signs ofgrowth (turbidity). The lowest concentration tested which inhibits thebacterial growth (tubes remain clear) is recorded as the minimalinhibitory test concentration (M.I.T.C.).

The compounds of Examples 22, 26, 42, 44, 45 and 47 have shownantibacterial activity in the above test, especially againstgram-positive organisms such as B. subtilis, Staph. aureus, and Strep.pyogenes.

I claim:
 1. Compound of the formula: ##STR23## wherein m and n are 0 or1 and the sum of m+n is at least 1;the R groups are the same ordifferent and are H or CH₃, and one of them can be C₂ -C₉ alkyl, phenyl,C₇ -C₁₀ phenylalkyl, furyl, thienyl, pyridyl, phenyl or C₇ -C₁₀phenylalkyl substituted on adjacent ring carbon atoms withmethylenedioxy, or phenyl or C₇ -C₁₀ phenylalkyl substituted on the ringwith 1, 2 or 3 substituents individually selected from methoxy, ethoxy,bromine, chlorine, fluorine, trifluoromethyl and C₁ -C₄ alkyl; R¹ ishydrogen, C₁ -C₄ alkyl, C₃ -C₅ alkenyl, C₃ -C₅ alkynyl, C₃ -C₆cycloalkyl, C₂ -C₄ alkoxycarbonyl, trifluoroacetyl or substituted C₁ -C₄alkyl where the substituent is C₃ -C₆ cycloalkyl, phenyl, phenylsubstituted on adjacent carbon atoms with methylene-dioxy, or phenylsubstituted with 1, 2 or 3 substituents individually selected frommethoxy, ethoxy, bromine, chlorine, fluorine, and trifluoromethyl; and Zis H, Cl or CH₃ ; and their pharmaceutically suitable salts.
 2. Thecompound of claim 11,2,8,9,10,11-hexahydro-9-methyl-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepineand its pharmaceutically suitable salts.
 3. The compound of claim 1(±)-1,2,8,9,10,11-hexahydro-4-phenyl-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-jk][4,1]benzoxazepineand its pharmaceutically suitable salts.
 4. A pharmaceutical preparationsuitable for use in warm-blooded animals consisting essentially of aneffective sedative amount of a compound of claim 1 and apharmaceutically suitable vehicle.
 5. A method for inducing sedation ina warm-blooded animal which comprises administering to the animal aneffective sedative amount of a compound of claim 1.